Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCC58QJ)

• DOT Name: Rapamycin-insensitive companion of mTOR (RICTOR)
• Synonyms: AVO3 homolog; hAVO3
• Gene Name: RICTOR
• Related Disease: Tourette syndrome
• UniProt ID: RICTR_HUMAN
• PDB ID: 5ZCS; 6ZWM; 6ZWO; 7PE7; 7PE8; 7PE9; 7TZO
• Pfam ID: PF14663 ; PF14666 ; PF14664 ; PF14665 ; PF14668
• Sequence:
  MAAIGRGRSLKNLRVRGRNDSGEENVPLDLTREPSDNLREILQNVARLQGVSNMRKLGHL
  NNFTKLLCDIGHSEEKLGFHYEDIIICLRLALLNEAKEVRAAGLRALRYLIQDSSILQKV
  LKLKVDYLIARCIDIQQSNEVERTQALRLVRKMITVNASLFPSSVTNSLIAVGNDGLQER
  DRMVRACIAIICELALQNPEVVALRGGLNTILKNVIDCQLSRINEALITTILHLLNHPKT
  RQYVRADVELERILAPYTDFHYRHSPDTAEGQLKEDREARFLASKMGIIATFRSWAGIIN
  LCKPGNSGIQSLIGVLCIPNMEIRRGLLEVLYDIFRLPLPVVTEEFIEALLSVDPGRFQD
  SWRLSDGFVAAEAKTILPHRARSRPDLMDNYLALILSAFIRNGLLEGLVEVITNSDDHIS
  VRATILLGELLHMANTILPHSHSHHLHCLPTLMNMAASFDIPKEKRLRASAALNCLKRFH
  EMKKRGPKPYSLHLDHIIQKAIATHQKRDQYLRVQKDIFILKDTEEALLINLRDSQVLQH
  KENLEWNWNLIGTILKWPNVNLRNYKDEQLHRFVRRLLYFYKPSSKLYANLDLDFAKAKQ
  LTVVGCQFTEFLLESEEDGQGYLEDLVKDIVQWLNASSGMKPERSLQNNGLLTTLSQHYF
  LFIGTLSCHPHGVKMLEKCSVFQCLLNLCSLKNQDHLLKLTVSSLDYSRDGLARVILSKI
  LTAATDACRLYATKHLRVLLRANVEFFNNWGIELLVTQLHDKNKTISSEALDILDEACED
  KANLHALIQMKPALSHLGDKGLLLLLRFLSIPKGFSYLNERGYVAKQLEKWHREYNSKYV
  DLIEEQLNEALTTYRKPVDGDNYVRRSNQRLQRPHVYLPIHLYGQLVHHKTGCHLLEVQN
  IITELCRNVRTPDLDKWEEIKKLKASLWALGNIGSSNWGLNLLQEENVIPDILKLAKQCE
  VLSIRGTCVYVLGLIAKTKQGCDILKCHNWDAVRHSRKHLWPVVPDDVEQLCNELSSIPS
  TLSLNSESTSSRHNSESESVPSSMFILEDDRFGSSSTSTFFLDINEDTEPTFYDRSGPIK
  DKNSFPFFASSKLVKNRILNSLTLPNKKHRSSSDPKGGKLSSESKTSNRRIRTLTEPSVD
  FNHSDDFTPISTVQKTLQLETSFMGNKHIEDTGSTPSIGENDLKFTKNFGTENHRENTSR
  ERLVVESSTSSHMKIRSQSFNTDTTTSGISSMSSSPSRETVGVDATTMDTDCGSMSTVVS
  TKTIKTSHYLTPQSNHLSLSKSNSVSLVPPGSSHTLPRRAQSLKAPSIATIKSLADCNFS
  YTSSRDAFGYATLKRLQQQRMHPSLSHSEALASPAKDVLFTDTITMKANSFESRLTPSRF
  MKALSYASLDKEDLLSPINQNTLQRSSSVRSMVSSATYGGSDDYIGLALPVDINDIFQVK
  DIPYFQTKNIPPHDDRGARAFAHDAGGLPSGTGGLVKNSFHLLRQQMSLTEIMNSIHSDA
  SLFLESTEDTGLQEHTDDNCLYCVCIEILGFQPSNQLSAICSHSDFQDIPYSDWCEQTIH
  NPLEVVPSKFSGISGCSDGVSQEGSASSTKSTELLLGVKTIPDDTPMCRILLRKEVLRLV
  INLSSSVSTKCHETGLLTIKEKYPQTFDDICLYSEVSHLLSHCTFRLPCRRFIQELFQDV
  QFLQMHEEAEAVLATPPKQPIVDTSAES
• Function: Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Plays an essential role in embryonic growth and development.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway:
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Regulation of TP53 Degradation (R-HSA-6804757)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tourette syndrome	DISX9D54	No Known	Unknown	[1]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Rapamycin-insensitive companion of mTOR (RICTOR).	[2]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Rapamycin-insensitive companion of mTOR (RICTOR).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rapamycin-insensitive companion of mTOR (RICTOR).	[7]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[8]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[12]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[13]
MLN4924	DMP36KD	Phase 3	MLN4924 increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[16]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[18]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[19]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[20]
SB216763	DMIYFQ5	Investigative	SB216763 increases the expression of Rapamycin-insensitive companion of mTOR (RICTOR).	[14]

References

• [1] Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing. Am J Med Genet B Neuropsychiatr Genet. 2017 Oct;174(7):712-723. doi: 10.1002/ajmg.b.32559. Epub 2017 Jun 13.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [8] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [9] The human myometrium differentially expresses mTOR signalling components before and during pregnancy: evidence for regulation by progesterone. J Steroid Biochem Mol Biol. 2014 Jan;139:166-72. doi: 10.1016/j.jsbmb.2013.02.017. Epub 2013 Mar 26.
• [10] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [14] Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. J Biol Chem. 2015 May 29;290(22):14120-9. doi: 10.1074/jbc.M114.633057. Epub 2015 Apr 20.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene. 2008 Nov 27;27(56):7106-17. doi: 10.1038/onc.2008.318. Epub 2008 Sep 8.
• [20] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.